title: Evidence for a repertoire of functional untolerized CD4+ T cells specific for melanoma-associated antigens.
abstract: Active vaccination against melanoma requires tolerance break as melanoma-associated antigens (MAA) used in vaccine formula are mostly self-antigens. While tolerance to MAA in the CD8(+) T cell compartment is well characterized, it is still not the case for the CD4(+) T cell compartment. Here, we analysed CD4(+) T cell tolerance to such antigens in mice genetically engineered to express ovalbumin (OVA) in melanocytes (Tyr-OVA mice). When we crossed Tyr-OVA mice with DO11.10 and OT-II mice transgenic for an OVA-specific TCR restricted by MHC class II, we observed different tolerization levels. Central tolerance was complete for high avidity DO11.10 CD4(+) T cells, but absent for low avidity OT-II CD4(+) T cells. OT-II CD4(+) T cells also ignored OVA in the periphery of Tyr-OVA mice, albeit being potently reactive to vaccination. OVA challenge in single transgenic Tyr-OVA mice confirmed the existence of OVA-reactive CD4(+) T cells with the induction of efficient T helper cells for antibody production and anti-tumour T cell response. In total, our study demonstrates the existence of low avidity MAA-specific CD4(+) T cells escaping by ignorance central and peripheral tolerance, but valuable in the context of vaccination against melanoma.
authors.affiliation: Hematology Unit, University Hospitals, Geneva, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Huber
authors.forename: M
authors.initials: M
authors.lastname: Benkhoucha
authors.forename: B
authors.initials: B
authors.lastname: Huard
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D007108:Immune Tolerance; D008544:Melanocytes / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D010047:Ovalbumin